(a) Field
The subject matter disclosed generally relates to compositions, and more specifically to transdermal or topical compositions comprising nitric oxide amino acid ester compounds improving vascular circulation, and prophylaxis or treatment of a condition associated with impaired blood circulation.
(b) Related Prior Art
The decline in cardiovascular morbidity and mortality in the United States over the past three decades has been the result of significant advances in research on cardiovascular disease mechanisms and therapeutic strategies. However these advances have not been as pronounced in the treatment of peripheral vascular insufficiencies due to the onset of various ailments such as diabetes, and arterioscleriosis. These peripheral insufficiencies result in various disease states and even amputation. The incidence of amputation related to peripheral vascular insufficiency and its related conditions is associated with significant costs and significant impairment to the individual. Worldwide prevalence estimates of amputation is difficult to obtain, mainly because amputation receives very little attention and resources in countries where survival is low (Aleccia 2010). The overall rates of amputation due to trauma or malignancy are decreasing while the incidence of dysvascular amputations is rising (Dillingham et al. 2002). Amputations due to dysvascular disease accounts from roughly 54% of limb loss cases in the United States, while traumatic amputations account for 45% of loss (Aleccia 2010). The number of lower limb amputations is expected to increase in the United States to 58,000 per year by 2030 (Cutson and Bongiorni 1996; Fletcher et al., 2002), with nearly 75% occurring in those aged 65 and older (Clark et al. 1983).
The compounds administered for the treatment of diuresis, peripheral vascular disease (also known as peripheral arterial disease) and diseases resulting from oxidative and/or endothelial dysfunctions often result in toxic, chronic and/or debilitating side effects. Cardiovascular compounds such as ACE inhibitors, beta-adrenergic blockers, antithrombotic, thrombolytics, anticoagulants, antiplatelet agents and vasodilator compounds or anti-hyperlipidemic compounds, show, for example, respiratory toxicity resulting in asthma and/or bronchitis, renal impairment, liver toxicity and other side effects. Hence there is a need in the art for compounds that have improved efficacy, lower toxicity and that can be used at low dosages. The invention is directed to these, as well as other, important ends.
An ulcer is a sore on the skin or a mucous membrane, accompanied by the disintegration of tissue. Ulcers can result in complete loss of the epidermis and often portions of the dermis and even subcutaneous fat. An ulcer that appears on the skin is often visible as an inflamed tissue with an area of reddened skin. A skin ulcer is often visible in the event of exposure to heat or cold, irritation, or a problem with blood circulation such as the cardiovascular diseases mentioned above. For example, due to lack of mobility, there is a prolonged pressure on the tissues, which causes a stress in the blood circulation which is transformed to a skin ulcer, commonly known as bedsores or decubitus ulcers. Ulcers often become infected, and pus forms.
Nitric oxide (NO) donor molecules are well known vasodilators that can contribute to improving blood circulation in an ulcerated area. Molecules such as nitroglycerin have been used to treat such conditions. However, in the case of nitroglycerin, there are several drawbacks to the manufacture, storage and use of nitroglycerin. Nitroglycerin is an explosive compound that is difficult to produce and stabilize. It is inherently unstable over the long term resulting in a maximum shelf life of a product containing of about six months.
A major drawback to the long term usage of nitroglycerin for the treatment of diseases is that the metabolic pathway for the liberation of nitric oxide from nitroglycerin occurs in the mitochondria, utilizing the aldehyde dehydrogenase 2 enzyme. The liberation of large amounts of nitric oxide within the mitochondria from the use of nitroglycerin proves to be toxic to the mitochondria over time and eventually causes extensive metabolic disruption. Also, certain classes of patient suffering from nitric oxide deficiencies, mainly of Asian descent, have been shown to carry a recessive allele of the gene producing aldehyde dehydrogenase 2 which renders them non-responsive to the use of nitroglycerin.
Therefore there still exists a need for an efficient replacement molecules for nitroglycerin, but that would not possess the negative aspects of nitroglycerin, such as poor stability, short half life and inherent toxicity. The use of such replacement molecules for the treatment for dermatological ulcers, is highly desirable.
It is thus desirable to provide a composition and method for improving vascular circulation, and prophylaxis or treatment of a condition associated with impaired blood circulation, which involves an alternative compound to nitroglycerin, and does not require any special operational procedures other than the application of a composition.
It is thus desirable to provide a composition and method for improving vascular circulation, and prophylaxis or treatment of a condition associated with impaired blood circulation which contains an alternative compound to currently existing vasodilator compounds, and does not require any special operational procedures other than the application of a composition.